Diazepine derivatives of dithiocarboxylates as dopamine - beta - hydroxylase inhibitors

ABSTRACT

PIPERAZINE AND DIAZEPINE DERIVATIVES OF DITHIOCARBOXYLATES AND DISULFIDES HAVING THE GENERAL FORMULA   R1-N&lt;(-CH2-CH2-N(-C(=S)-S-R2)-(CH2)N-)(-R3)(-R4)   A PROCESS FOR THEIR PREPARATION AND A METHOD FOR THE INHIBITION OF THE ENZME DOPAMINE-B-HYDROXYLASE WHEREIN A THERAPEUTICALLY EFFECTIVE DOSE OF A PHARMACEUTICALLY ACCEPTABLE PREPARATION OF A COMPOUND OF THE SAID GENERAL FORMULA IS ADMINISTERED ORALLY, RECTALLY OR BY MEANS OF AN INJECTION TO PRODUCE A SEDATIVE EFFECT.

UiiitedStates Patent Oifice 3,644,623 Patented Feb. 22, 1972 US. Cl. 424244 Claims ABSTRACT OF THE DISCLOSURE Piperazine and diazepine derivatives of dithiocarboxylates and disulfides having the general formula a process for their preparation, and a method for the inhibition of the enzyme dopamine-p-hydroxylase wherein a therapeutically effective dose of a pharmaceutically acceptable preparation of a compound of the said general formula is administered orally, rectally or by means of an injection to produce a sedative effect.

The present invention relates to a method to inhibit the enzyme dopamine-fl-hydroxylase, compounds having such an eifect, a method for the manufacture of such compounds and pharmaceutical preparations containing them.

The object of the present invention is to provide a compound by means of which there takes place an inhibition of the hydroxylation of dopamine [/8-(3,4-dihydroxyphenyl) ethylamine] to noradrenaline [l-a-(aminomethyl)-3,4-dihydroxybenzyl alcohol] and there is obtained a psychotherapeutic effect.

It has previously been known that tetraethylthiuram disulfide and its metabolite diethyldithiocarbamate, and the structurally similar compound phenylethyl dithiocarbamate, are dopamine-,H-hydroxylase inhibitors. It has now been found possible according to the present invention to obtain a considerably higher enzyme inhibiting activity than by means of previously known compounds by administering to living beings an elfective dosage of a compound of the general formula R -N N-CSSR2 wherein n denotes the number 2 or 3, R denotes a straight or branched, saturated or unsaturated alkyl group having at most 6 carbon atoms, R and R are selected from the group consisting of hydrogen and methyl and R denotes hydrogen, sodium, or another non-toxic cation, or the group wherein 11, R R and R have the same significance as in the general formula.

The present invention relates in particular to new compounds which are characterized by the general formula 1 N-csswherein n, R R and R have the same significance as above, and when (1) n is 2, (2) R is sodium and (3) R is methyl, ethyl, n-propyl, n-butyl, amyl or isopropyl: at least one of R and R must be methyl. The same conditions, that is, that at least one of R and R must be methyl, also obtain when (1) n is 2, (2) R is hydrogen and (3) R is methyl or ethyl.

The expression alkyl means in this connection primary, secondary and tertiary alkyl groups having straight as well as branched chains, the number of carbon atoms being as indicated, at most six. The alkyl group is preferably a methyl, ethyl, n-propyl, amyl, isopropyl or secondary butyl group, or the like.

Certain groups of these new compounds have been found to be particularly efiective for inhibiting the hydroxylation of dopamine to noradrenaline. One such group are those compounds of the general formula R N N cssn v R aha wherein n is 2, R is methyl, ethyl, n-propyl, isopropyl, butyl or allyl, both R and R are hydrogen and R is hydrogen, sodium or the group R -N N-css wherein R R and R have the same meaning as indicated above. Another such group of new compounds of the general formula occurs when n is 2, R is methyl, ethyl, isopropyl, sec-butyl, amyl or allyl, R is hydrogen or sodium, R is 2- or 3-methyl and R is hydrogen. Also included is the group of compounds wherein n is 2, 'R is methyl or isopropyl, R is once again hydrogen or sodium, R is 2- or 3-methyl and R is 5- or 6-methyl. Lastly, is the group of new compounds of the above stated formula wherein n is 3, R is methyl, R and R are both hydrogen and R is either hydrogen or the group R3 1 l R N N css 7A (cs wherein R R and R have the same meaning as indicated above.

These new compounds including those preferred are manufactured as follows: A compound of the general formula is reacted with carbon disulfide, alone or in the presence of a compound of the formula RZ, wherein R denotes sodium, or another non-toxic cation, and Z denotes an anion, such as, e.g., OH, C and the like, for the formation of a compound of the general formula N N cssa R which thereupon, if compounds are desired where R denotes hydrogen, is reacted with an acid, or if compounds are desired where R denotes the group is oxidized for the formation of a compound of the general formula wherein n, R R and R have the same significance as indicated above.

In order to manufacture compounds of the general formula above, and in the cases where R denotes the group one starts preferably with the water soluble salt of the general formula in a pharmaceutically acceptable carrier, which may comprise a solid, a semi-solid, a liquid or a capsule. These preparations normally contain between 0.1 and percent by weight for preparations intended for injections and between 2 and 50 percent by Weight for preparations intended for oral administration.

To produce a pharmaceutical preparation containing a compound of the present invention, in the form of dosage units for oral administration, such a compound may be mixed with a solid pulverulent carrier, for example, lactose, 'saccharose, sorbitol, mannitol, starch, such as potato starch, cornstarch, amylopectin, laminaria powder or a citrus pulp powder, celuose derivatives or gelatin. The compound may also include a lubricant such as magnesium or calcium stearate or a Carbowax or other polyethylene glycol wax, the final mixture being compressed to form tablets. When coated tablets are required, the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, talcum and/or titanium dioxide. Alternatively, the tablets may be coated with a lacquer dissolved in a volatile organic solvent or a mixture of organic solvents. Dyestuffs may be added to these coatings, for distinction between tablets containing different contents of the active compound. For the preparation of soft gelatine capsules (pearlshaped, closed capsules) consisting of gelatin and, for example, glycerol and similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatin capsules may contain granulates of the active substance in combination with solid pulverulent carriers such as lactose, saccharose, mannitol, starches (e.g., potato starch, cornstarch or amylopectin), cellulose derivatives or gelatin. Dosage units for rectal administration may comprise suppositories comprising the active compound in admixture with a neutral fatty base or gelatin capsules comprising the active compound in admixture with vegetable oil or paraflin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing from about 2 to about 20 percent by weight of the active compound, sugar and a mixture of ethanol, water and glycerol, propeneglycol and, in addition, flavoring agents, saccharine and/or carboxymethyl cellulose as a thickening agent.

For parenteral administration by means of injections, the preparations according to the invention preferably comprise an aqueous solution of the active compound in a concentration of 0.5 to 10 percent by Weight, and further, a stabilizing agent and/or a buffering agent. For convenience, it might be desirous to enclose the dosage units of the solution in ampoules.

The dosage amount for one patient depends upon the active compounds used, the manner of administration and the desired therapeutic effect. Generally, the dose varies from 0.5 mg. to about 7 mg. per kilo of the body weight at a peroral one-shot dose.

Compounds of the general formula where n, R R and R have the significance as indicated above, may be manufactured in various Ways. In cases when R and R are hydrogen or a methyl in the 2- and/ or 6- or 7-position respectively in relation to R the following reaction scheme could preferably be followed:

11 x R N N R 1 H e1. on a R N N a BAX 2')n wherein R denotes a protecting group, such as, for example, an alkoxycarbonyl, benzyl, trityl, acyl, nitroso or sulphonyl group (cf. Examples 1, 2, 7, 8 and 10 infra).

When R and R denote hydrogen, it is advisable to start with the hemisalt of the above diamine to give the following reaction:

wherein HA could denote an inorganic as well as an organic acid.

When at least one of R and R denotes a methyl group in 3- or 5-position in relation to R the reaction preferably follows the following reaction scheme:

(cf. the Examples 3, 4, 5 and 6 in the following). During the reaction between the amine and carbon disulfide in an inert solvent, such as, for example, ether, the free acid is obtained R N N cssrr present as an internal salt 1 H (CI-12):: R

which then, if a compound is desired in which R denotes sodium, or another non-toxic cation other than hydrogen, may be reacted with the hydroxide of the desired cation in an equivalent quantity, and the corresponding salt will be formed.

For a direct formation of the compound wherein R denotes sodium or another non-toxic cation, the amine is reacted with carbon disulfide in the presence of the hydroxide of the desired cation. If the free acid is desired, the salt formed may then be reacted with an acid, such as acetic acid, and the free acid will precipitate as an internal salt.

The present invention will now be described with reference to the following examples without being in any way restricted thereto. Therefore, though the examples disclose the preparation of compounds wherein R is an alkyl or alkylene group, it is intended to include the processes, compounds and compositions where R is alkyne as well.

EXAMPLE 1 g. (0.05 mol) of 2-methylpiperazine were dissolved in 700 ml. of water to which solution was added a small quantity of benzylorange as an indicator. The solution was acidified with concentrated hydrochloric acid to a clear color change to orange, and than the excess acid was neutralized with a saturated sodium acetate solution until a color change to yellow. 78 ml. (1 mol) of chloro formic acid methyl ester was then added drop by drop, with a careful stirring, the pH-value being adjusted by means of a saturated sodium acetate solution. The solution thus obtained was extracted by means of ether and the water phase was saturated in coolness with potassium carbonate and then the base was extracted by means of ether, which was dried over anhydrous sodium sulfate. The ether was evaporated and the residue was distilled. 95.5 g. of 1-carbomethoxy-3-methylpiperazine was obtained at IDS-107 C./ 10 mm. Hg. The equivalent weight was calculated to be 158 While determined by analysis to be 160.

30.4 g. (0.192 mol) of the product obtained were refluxed with stirring for 17 hours with 15.6 ml. (0.195 mol) of ethyl iodide and 27.6 g. (0.2 mol) of potassium carbonate in 350 ml. of absolute alcohol. The potassium iodide formed and the remaining quantity of potassium carbonate was filtered off and washed with absolute ethanol. The filtrate was evaporated in a vacuum and the residue dissolved in ether. The remaining quantity of salts was sucked off and the ether was evaporated. The residue was distilled, and 30 g. of 4-ethyl-l-carbomethoxy-B-methylpiperazine were obtained at 110-111" C./ 10 mm. Hg.

30 g. of the product were refluxed in ml. of concentrated hydrochloric acid for three days and then the excess hydrochloric acid was boiled oif. To the residue, 4-ethyl-3-methylpiperazine hydrochloride, there was added 150 ml. of a 30% solution of sodium hydroxide, the solution then being saturated with solid sodium hydroxide. The amine phase was dissolved in ether and dried over anhydrous sodium sulfate. The ether was evaporated, and 15.3 g. of raw 1-ethyl-2-methylpiperazine were obtained.

To an iced solution of 10 ml. of carbon disulfide in 150 ml. of ether, 15.3 g. of raw 1-ethyl-2-methylpiperazine in 100 ml. of ether were added drop by drop while stirring. The mixture was stirred for 30 minutes and a precipitate formed, raw 4-ethyl-3-methyl-l-piperazinedithiocarboxylic acid, which was filtered ofi and washed with ether. The melting point was 165167 C. (subl.). The yield was 18.1 g. The product was recrystallized from water and had a 175-176 C. melting point (subL). The yield was 4.3 grams.

Analysis in percent.-Calculated: C, 47.02; H, 7.89; N, 13.71; S, 31.38. Found: C, 46.7; H, 7.84; N, 13.8; S. 31.4.

EXAMPLE 2 34.4 g. (0.2 mol) of 1-carbethoxy-3-methylpiperazine, which was obtained analogously to the l-carbomethoxy- 3-methylpiperazine according to Example 1, 17.3 ml. (0.2 mol) of allyl bromide, 28 g. (0.2 mol) of potassium carbonate and 5 g. of potassium iodide in 300 ml. of ethanol were refluxed while stirring for 24 hours. The salts were filtered off and washed with ethanol and the filtrate was evaporated in a vacuum. The residue was dissolved in ether and the remaining salts were sucked off. The ether was then evaporated and the residue distilled. 30.8 g. of 4-allyl-1-carbethoxy-3-methylpiperazine were obtained at 132134 C./ mm. Hg. The equivalent weight was calculated to be 212.3 while by an analysis found to be 214.

30.8 g. of the product were refluxed in 150 ml. of concentrated hydrochloric acid for three days. The hydrochloric acid was evaporated in a vacuum, and to the residue 150 ml. of a 30% solution of sodium hydroxide was added and the solution saturated with solid sodium hydroxide. The amine phase was dissolved in ether and dried over anhydrous sodium sulfate whereupon the ether was evaporated and the residue distilled. 14.5 g. of l-allyl- Z-methylpiperazine was obtained at 7880 C./ mm. Hg. An analysis gave the equivalent weight of 74 in relation to the calculated weight of 70.12.

14.5 g. (0.104 mole) of the product was dissolved in 52 ml. of 2 N sodium hydroxide with subsequent addition of 6.3 ml. (0.104 mol) of carbon disulfide. The mixture was evaporated in a vacuum after stirring at room temperature for 30 minutes and the residue was recrys tallized from ethanol ether. 15.9 g. of s0dium-4-allyl-4- methyl 1 piperazinedithiocarboxylate dihydrate with a melting point of 9194 C. was obtained.

Analysis in percent.-Calculated: C, 39.4; H, 6.98; N, 10.21; S, 23.37. Found: C, 38.8; H, 7.00; N, 10.3; S, 23.4.

EXAMPLE 3 50 g. (0.5 mol) of Z-methylpiperazine, 100 ml. (1.06 mol) of isopropyl bromide, 70 (0.5 mol) of potassium carbonate, g. of potassium iodide in 350 ml. of absolute ethanol were refluxed while stirring until the formation of carbon dioxide ceased, which takes place within two days. The salts were filtered off and washed with ethanol. The filtrate was evaporated in a vacuum, the residue dissolved in ether and the remaining salts filtered off. The ether was evaporated and the residue distilled. 30.8 g. of 1-isopropyl-3-methy1piperazine were obtained at 6669 C./ 10 mm. Hg. The equivalent weight was calculated to be 71.13 and was determined by an analysis to be 72.

30.8 g. of the product were reacted under intense stirring with 14 ml. of carbon disulfide in 110 ml. of 2 N sodium hydroxide. Water was added to the solution to a total value of 800 ml. with subsequent adjustment of the hydrogen ion concentration to a pH-value of 6 by means of an addition, drop by drop, of acetic acid during intense stirring and ice cooling. After minutes the precipitate formed was sucked off, it being 4-isopropyl-2- methyl-l-piperazinedithiocarboxylic acid which was washed with water, ethanol and ether. The melting point was determined to be 125-128 C. The yield was 20.6 g.

The product was dissolved in 800 ml. of dilute sodium hydroxide and reprecipitated by means of acetic acid. The melting point was 128-130 C. The yield was 8.5 g.

Analysis in percent-Calculated: C, 49.50; H, 8.31; N, 12.83; S, 29.36. Found: C, 48.6; H, 8.49; N, 13.0; S, 29.7.

EXAMPLE 4 A mixture of g. (0.5 mol) of Z-methylpiperazine, ml. of 2-bromobutane, g. (0.5 mol) of potassium carbonate, 5 g. of potassium carbonate, 5 g. of potassium iodide, and 350 ml. of methyl ethyl ketone was refluxed during stirring for 12 hours. The potassium bromide formed and the remaining quantities of potassium carbonate and potassium iodide were filtered off and washed by means of ethanol. The filtrate was then evaporated in a vacuum and the residue dissolved in ether. The remaining quantity of salts was sucked 00?, the ether evaporated and the residue distilled. 24.5 g. of 1-sec-butyl-3- methyl-piperazine were obtained at 77-79 C./mm. Hg. The equivalent weight was calculated to be 78.14 while found by analysis to be 81.

24.5 g. of the product reacted with 10 ml. of carbon disulfide in the presence of ml. of 2 N sodium hydroxide. Water was added to the solution to a total volume of 300 ml. and the solution acidified by addition of acetic acid to a pH-value of 6. The precipitate which comprised 4 sec-butyl 2 methyl-piperazinedithiocarboxylic acid, was sucked 011 and washed with ice water and ether. The melting point was 82-85 C. The yield was 26.5 g.

After a reprecipitation with acetic acid from 400 ml. of sodium hydroxide, 11.9 g. with a melting point 85- 87 C. were obtained.

Analysis in percent.-Calculated: C, 51.68; H, 8.67; N, 12.06; S, 27.59. Found: C, 51.5; H, 8.64; N, 12.1; S, 27.1.

EXAMPLE 5 19.7 g. of l-alkyl-3-methylpiperazine, which was obtained analogously to 1-sec-butyl-3-methylpiperazine according to Example 4 and distilled at 71-75 C./10 mm. Hg, was reacted with 8.5 ml. of carbon disulfide in the presence of 69 ml. of 2 N sodium hydroxide. The solution was diluted to a volume of 500 ml. by an addition of water and the internal salt was precipitated by means of acetic acid at pH-value 7 and then sucked off. The product, 4 allyl Z-methyl-1-piperazinedithiocarboxylic acid, melted at 85-87 C. and had a weight of 15.5 g. 4- allyl 2-methyl-1-piperazinedithiocarboxylic acid was reprecipitated from 700 ml. of diluted sodium hydroxide by means of acetic acid. The melting point was 88-89 C. The yield was 2.2 g.

Analysis in percent.Calculated: C, 49.96; H, 7.45; N, 12.95; S, 29.64. Found: C, 50.3; H, 7.24; N, 12.9; S, 29.8.

EXAMPLE 6 17.0 g. of 1-isopropyl-3,S-dimethylpiperazine with a calculated equivalent weight of 78.14, an analysis weight of 81, a boiling point of 65-66 C./ 10 mm. Hg and prepared as 1-isopropyl-3-methylpiperazine according to Example 3, was reacted with 6.61 ml. of carbon disulfide in 54.5 ml. of 2 N sodium hydroxide. The mixture was evaporated in a vacuum and the residue recrystallized from ligroinethanol. The melting point was -138 C. The yield was 17.5 g.

The product was dissolved in ethanol and petroleum ether was added in an amount giving a slight precipitation. The mixture was left at 0 C. over night and a precipitate formed which was filtered off (about 0.5 g. of contaminations with a melting point of 250 C.), The product, sodium 4 isopropyl-2,6-dimethyl-l-piperazinedithiocarboxylate, with 1.5 crystal water was then precipitated by means of ether from the mother liquor. The melting point was 136-138 C. The yield was 2.1 g.

Analysis in percent.-Calculated: C, 42.68; H, 7.88; N, 9.99; S, 22.79. Found: C, 42.8; H, 7.87; N, 10.1; S, 22.9.

EXAMPLE 7 62.5 g. (0.362 mol) of 1 carbethoxy-3-methylpiperazine, 68 ml. (0.4 mol) of isopropyl bromide, 51 g. of potassium carbonate and 10 g. of potassium iodide in 300 ml. of methyl-ethyl ketone was refluxed with stirring for 4 days. The salt was filtered 01f and washed with ethanol, and the filtrate was evaporated in a vacuum. The remaining salt was precipitated with ether. The ether was evaporated and the residue distilled. 52.3 g. of 4- isopropyl 1 carbethoxy 3 methylpiperazine were obtained at 131133 C./ 10 mm. Hg. The equivalent weight was found to be 218, while calculated to be 214.3.

52.3 g. of the product were refluxed with 250 ml. of concentrated hydrochloric acid for three days and the solution was evaporated in a vacuum. 150 ml. of 30% sodium hydroxide was added to the residue. The amine phase was dissolved in ether and dried over sodium sulfate. The ether was evaporated and the residue distilled. 24.6 g. of 1-isopropyl-Z-methylpiperazine were obtained at 70-71 C./10 mm. Hg.

24.6 g. of the product were reacted with 11 m1. of carbon disulfide in the presence of 87 ml. of 2 N sodium hydroxide. The solution was evaporated in a vacuum and the product, sodium-4-isopropyl-3-methyl-l-piperazinedithiocarboxylate dihydrate, was recrystallized from ethanol-isopropyl ether. The melting point was 133135 C. The yield was 10.5 g.

Analysis in percent (raw product).-Calculated: C, 39.11; H, 7.66; N, 10.13; S, 23.20, Found: C, 41.6; H, 7.85; N, 10.5; S, 23.6.

EXAMPLE 8 82.5 g. of 4-amyl-1-carbethoxy-3-methylpiperazine having a boiling point of 117-l20 C./ 15 mm. Hg, which were obtained analogously to 4-allyl-1-carbethoxy-3- methylpiperazine according to Example 2, were refluxed in 380 ml. of concentrated hydrochloric acid for three days and the solution was subsequently evaporated in a vacuum. 300 ml. of 30% sodium hydroxide solution were added and the amine phase formed was dissolved in ether and dried over anhydrous sodium sulfate, The ether was evaporated and the residue distilled. 42.4 g. of I-amyl-Z-methylpiperazine were obtained at 99100 C./10 mm. Hg.

42.4 g. of the product were reacted with 15 ml. of carbon disulfide in 124 ml. of 2 N sodium hydroxide. The solution was evaporated in a vacuum and the residue was crystallized twice from ethyl acetate. The product, sodium-4-amyl-3-methyl-1 piperazinedithiocarboxylate, was dissolved in 500 ml. of water. 4-amyl-3-methyl-1- piperazinedithiocarboxylic acid was precipitated by means of acetic acid at pH-value 7. The melting point was 112114 C, The yield was 15.5 g.

Analysis in percent.-Calculated: C, 53.61; H, 9.00; N, 11.37; S, 26.02. Found: C, 53.5; H, 9.05; N, 11.3; S, 25.9.

EXAMPLE 9 21.6 g. of sodium-4-methyl-l-piperazinedithiocarboxylate were dissolved in 25 ml. of N sodium hydroxide and 50 ml. of water, While stirring, a solution of 14.5 grams of ammonium persulfate in 50 ml. of water was added drop by drop during cooling with ice. A precipitate formed and was filtered 01f, washed with Water and air dried. The precipitate, bis-(4-methtyl-l-piperazinylthiocarbonyl) disulfide had a melting point of 142l43 C. and had a weight of 12.5 g.

Analysis in percent.-Calculated: C, 41.11; H, 6.33; N, 15.98; S, 36.58. Found: C, 41.2; H, 6.36; N, 16.1; S, 36.7.

10 EXAMPLE 1o 57 g. (0.5 mol) of 2.6-dimethyl piperazine, and a small amount of benzylorange indicator, were dissolved in 150 ml. of water. Concentrated hydrochloric acid was added in such an amount that there was obtained a color change to orange. Excess hydrochloric acid was neutralized with sodium acetate. Chloroformic acid ethyl ester was then added, drop by drop while stirring, in an amount of 53 ml. (0.55 mol) with the addition of sodium acetate to adjust pH-value. The solution obtained was acidified with concentrated hydrochloric acid and extracted with ether. The water phase was neutralized with 30% sodium hydroxide and saturated with potassium carbonate. The amine phase formed was dissolved in ether and the water phase was ether extracted. The collected ether phase was then dried over anhydrous sodium sulfate and distilled. 58.0 g.'of 1-carbethoxy-3,5-dimethylpiperazine were obtained at -87 C./1 mm. Hg.

58.0 g. (0.31 mol) of the product were added to a mixture of 30 ml. of formic acid, 28 ml. 35% formaldehyde and 4 ml. of water while stirring and cooling by means of ice. The solution was left for 15 hours at C, and then acidified with concentrated hydrochloric acid and evaporated in a vacuum.

The residue, 1-carbethoxy-3,4,5-trimethylpiperazine hydrochloride, was refluxed in 200 ml. of concentrated hydrochloric acid for three days with subsequent evaporation of the solution in a vacuum. 250 ml. of 30% sodium hydroxide were then added and the amine phase formed was dissolved in ether, dried over anhydrous sodium sulfate and distilled. 20.3 g. of 1,2,6-trimethylpiperazine were obtained at 174-176" C./760 mm. Hg.

20.3 g. (0.158 mol) of the product were reacted with 10 ml. of carbon disulfide in 80 ml. of 2 N sodium hydroxide, The solution was evaporated in vacuum and the residue was recrystallized twice from ethanol-ether. The final product, sodium-3,4,5-trimethyl-l-piperazinedithiocarboxylate, melted at 166-169" C. and had a weight of 12.6 g.

Analysis in percent.Calculated: C, 42.45; H, 6.68; N, 12.38; S, 28.33. Found: C, 42.3; H, 6.99; S, 27.9.

EXAMPLE 11 To a solution of 5 ml. of carbon disulfide in 75 ml. of dry ether, 5 g. of l-ethyldiazepine in 75 ml. of dry ether was added drop by drop while cooling in ice and with efficient stirring. After 15 minutes the precipitate obtained was sucked 01f and washed with ether. The product, 4-methyl-1-diazepinedithiocarboxylic acid had a weight of 6.5 g. and a melting point of 201202 C. (subl.).

Analysis in percent.Ca1culated: C, 44.17; H, 7.41; N, 14.72; S, 33.69, Found: C, 44.0; H, 7.36; N, 14.8; S, 33.6.

EXAMPLE 12 30.00 g. (0.263 mol) of l-methyldiazepine dissolved in ml. of ether was added, drop by drop, to 25 ml. of carbon disulfide dissolved in 150 ml. of ether. The precipitate obtained was sucked off and washed with ether. The residue, 39 g. of 4-methyl-l-diazepinedithiocarboxylic acid, had a melting point of 200-202 C. (subl.).

38 g. (0.2 mol) of 4-methyl-1-diazepinedithiocarboxylic acid were dissolved in a solution of 10 g. (0.25 mol) sodium hydroxide in 200 ml. of water while stirring. During stirring and cooling in ice, a solution of 27.5 g. (0.12 mol) of ammonium persulfate in 75 ml. of water was added drop by drop. The stirring continued for 30 minutes after which the semicrystalline product obtained was dissolved in benzene and dried over sodium sulfate. The benzene was evaporated in a vacuum and the residue was dissolved in ethanol and boiled together with active carbon for 10 minutes. The solution was filtered hot and the filtrate was evaporated in a vacuum. The residue, a light yellow oil, was triturated with petroleum ether, after which it easily crystallized. The product, bis-(4-methyl- Table 2 shows the biological activity of compounds according to the present invention in certain behavioral experiments performed on mice. The compounds were injected intraperitoneously into the mice in groups of six and the contents of noradrenaline in the brain were determined 2, 4, and 8 hours after the injection. The determinations then were carried out according to Bertler et a1., Acta physiol. Scand. 44, 273 (1958). The values indicated in Table 2 give the contents of noradrenaline in the brain in percent of the normal contents of noradrenaline, which was found to be 0.45 :0.009 mg./ g. upon the TABLE 1 Analysis Calculated Found M.P. n R R R R C.) C H N S C H N S 2 CH2=CHCH- H H H 175 47.49 6.97 13.84 31.69 47.0 7.05 13.8 31.7 2 C a H 3CH3- H 170 44.17 7.41 14.72 33.69 44.0 7.35 14.8 33.5 2 CH H 2CH 5-CH3 160162 47.02 7.89 13.71 31.38 46.7 7.61 14.0 31.3

2 CzHzs- R H H 113.5-115 R -N -CSS 2 (OHa)2OH R H H 132-1335 47.25 7.44 13.87 31.53 46.4 7.12 14.1 31.0

Il -N NCSS Sub1.

The compounds according to the present invention basis of tests. A drop of the contents of noradrenaline have valuable therapeutic qualities due to their inhibition at normal or slightly increased dopamine contents in the of the enzyme dopamine-B-hydroxylase whereby the hydroxylation of dopamine to noradrenaline is inhibited and a sedative effect is obtained.

brain is then an indication of inhibition of dopamine-flhydroxylase. In all the doses reported in Table 2, the dopamine values of the brain were normal.

TABLE 2 Dose, n R R R R mgJkg. 2111s. 4hrs. shrs 2 CH H H H 37.45.6 62.9-13.3 72.0-3.7 2 CHz=CH-CH2 H H H 75 .6 69.0 83.2

2 C21I5- H H 75 42.74.3 57.2-15.8 79.03.4 2 CHa H 3CI'I3 H 75 49.7 68.2 89.9 2 2I-I H 3CH; H 75 59.7 84.6 80.2 2 CH3(CHz)z Na H H 75 55.1 77.9 94.2 2 (CHa)2CH Na. H II 75 61.9 53.2 68.3 2 CH -(CHz)3 Na. H H 75 58.9 68.4 95.1 2 Ha Na 3C-H; 5CHa- 75 68.0 87.4 109.3 2 (3113- H 2CH3 5-CH3- 75 58.2 55.5 99.6 2 CH3(CH2)4 H 3CHa- H 75 59.4 75.2 87.7 2 CHz=CH-CH Na 3CH3 H 75 63.8 73.9 99.5 2 (CH3)2CH H 2OH3 H 500 42.8 61.0 95.2

(C33) 2 /CH 11 2-CM3- H 52. 1 70. 5 85. 3

2 CHz=CHCHz- H 2-CHa- H 75 60.1 71.3 94.2 2 (OH3)2CH Na 2-CH:4 6-CH 500 60.9 61.0 82.2 2 (CHshCH- Na 3CHa' H 75 58.5 72.2 101.3 3 CH H H 75 35.9 37.7 49.9

2 CH R -N OSS N H 25 65.4 82.7 92.7

2 C H Same as above H H 150 57.4 65.9 66.4

2 (CH )zClI- do H H 150 54.1 37.2 65.4

3 CH3- R N\ N-CSS H H 50 28.5 18.3 29.0

As seen from Table 2, there was obtained considerably lower noradrenaline values by means of the compounds proposed according to the invention in relation to the normal contents of noradrenaline.

The intraperitoneal toxicity of the compounds of the present invention was determined on albino mice as follows:

Each tested compound was injected intraperitoneously into a group of ten mice and the animals were observed over a weeks period. The number of mice which were killed at each dose was registered and expressed in percent of the number of animals being injected with that particular dose. The dose that killed of the animals (LD was calculated from a logarithmic dose response graph.

The intraperitoneal toxicity of the compounds according to the present invention where n, R R R and R have the indicated meaning is reported in Table 3.

wherein n is 3, R is a straight or branched, saturated or unsaturated alkyl group having at most six carbon TABLE 3 1 50, n. R R R R mg./kg.

2 CH3- H H H 250 2 CH2=CHCH2 H H H 500 2 C2H5- H H H 400 2 CH3" H 3-CH3- H 500 2 CzHs- H 3-CH3 H 500 2 GHQ-(CH2)?- N8. H H 500 2 (CH 2CH- Na H H 500 2 GHr-(CHz) 3- Na H H 250 2 CHz- Na 3CHa' 5CH3 500 2 0113- H 2CH3-' 5CH3 500 2 CH3(CHz)4 H 3-CH3 H 200 2 CH2=CHCH2- Na 3-CH H 500 2 (CH3) zCH- H 2-CH; H 500 /CH H 2-CH3 H 450 C2Hn 2 CH2=CHCHz H 2CH H 500 2 (CH3) 2CH- Na 2CH3 6CH 500 2 (CH3) 2CH- Na 3CHa H 500 3 C 3- H H H 300 2 CH -RN CSS- H H 100 4 2 02115- Same as above H H 500 2 (CH 2CH do H H 600 3 CHaR N N-CSS H H 150 (CHQnR We claim: atoms, R and R are hydrogen or methyl, and R is 1. A method for the inhibition of the enzyme dopamine- ;B-hydroxylase, which comprises administering to living beings a therapeutically effective dose containing at least one compound of the general formula R N N CSSR hydrogen or sodium, in association with a pharmaceutical carrier.

7. A pharmaceutical preparation according to claim 6 wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, sec-butyl, amyl, and allyl.

8. A pharmaceutical preparation according to claim 6 wherein n is 3, R is methyl, and R R and R are hydrogen.

9. A pharmaceutical preparation according to claim 6 suitable for administration by injection which contains between 0.1% and active component by Weight.

10. A pharmaceutical preparation according to claim 6 suitable for oral administration which contains between 2 and 50% active component by weight.

References Cited Chem. Abst. 52, 15549 (1958).

STANLEY Y. FRIEDMAN, Primary Examiner U.S. Cl. X.R. 424250; 260239 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CGRRECTION PATENT NO. 3,644,623

DATED 1 February 22, 1972 v g mmg) Per Arvid Emil Carlsson et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Title, "DIAZEPINE" should read --HOMOPIPERAZINE; Col. 1, line 16, "diazepine" should read -homopiperazine; Col. 10, line 45, "l-ethyldiazepine" should read -lmethylhomopiperazine; Col. 10, line 49, "4-methylldiazepinedithiocarboxylic" should read -4methyllhomopiperazine-dithiocarboxylic-; Col. 10, line 56, "l-methyldiazepine" should read l-methylhomopiperazine; Col. 10, line 60, "4methylldiazepinedithiocarboxylic" should read -4methyllhomopiperazinedithiocarboxylic; Col. 10, line 62, "4methyl-ldiazepinedithiocarboxylic" should read -4-methyll-homopiperazine-dithiocarboxylic-; Col. 11, line 1, "l-diazepinylthiocarbonyl)disulfide" should read ll-homopiperazinylthiocarbonyl)disulfide-.

Signed and Scaled this Ninth D y f May 1978 @3 3 UNITED STATES PATENT OFFICE CERTIFICATEOF CORRECTION Patent No. 3,6 W, 23 Dated Ma 26, 1972 Inventor(s) Per Arvid Emil Carlsson et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 8 line 41, change "alkyl'v' to allyl ----5 Col. 8 line 6E, "change "6.6l" to 6.6 001. 9 line 39, change"82.5" to 82. 001. 9 l'ine 5E, change crystallized" to recrystallized C01. 12 Table 1, last figure under "Calculated N,

change "13.87" to 13.78

C01. 12 Table 2, l lth item under R change "2-CM to 19th iem, change "N" to H next to last item under "H hrs change "37.2" to 37.3 third column from left, change the heading "R H t R 5 C01. 13 Table 3, l lth item, insert 2 under "n heading.

Signed and sealed this 7th dayof November 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR I 7 ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

